Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation.
AKI
KLF15
PPARα
fatty acid oxidation
kidney fibrosis
proximal tubule
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
24
06
2021
revised:
06
08
2021
accepted:
20
08
2021
pubmed:
12
10
2021
medline:
15
12
2021
entrez:
11
10
2021
Statut:
ppublish
Résumé
Loss of fatty acid β-oxidation (FAO) in the proximal tubule is a critical mediator of acute kidney injury and eventual fibrosis. However, transcriptional mediators of FAO in proximal tubule injury remain understudied. Krüppel-like factor 15 (KLF15), a highly enriched zinc-finger transcription factor in the proximal tubule, was significantly reduced in proximal tubule cells after aristolochic acid I (AAI) treatment, a proximal tubule-specific injury model. Proximal tubule specific knockout of Klf15 exacerbated proximal tubule injury and kidney function decline compared to control mice during the active phase of AAI treatment, and after ischemia-reperfusion injury. Furthermore, along with worsening proximal tubule injury and kidney function decline, knockout mice exhibited increased kidney fibrosis as compared to control mice during the remodeling phase after AAI treatment. RNA-sequencing of kidney cortex demonstrated increased transcripts involved in immune system and integrin signaling pathways and decreased transcripts encompassing metabolic pathways, specifically FAO, and PPARα signaling, in knockout versus control mice after AAI treatment. In silico and experimental chromatin immunoprecipitation studies collectively demonstrated that KLF15 occupied the promoter region of key FAO genes, CPT1A and ACAA2, in close proximity to transcription factor PPARα binding sites. While the loss of Klf15 reduced the expression of Cpt1a and Acaa2 and led to compromised FAO, induction of KLF15 partially rescued loss of FAO in AAI-treated cells. Klf15, Ppara, Cpt1a, and Acaa2 expression was also decreased in other mouse kidney injury models. Tubulointerstitial KLF15 independently correlated with eGFR, PPARA and CPT1A appearance in expression arrays from human kidney biopsies. Thus, proximal tubule-specific loss of Klf15 exacerbates acute kidney injury and fibrosis, likely due to loss of interaction with PPARα leading to loss of FAO gene transcription.
Identifiants
pubmed: 34634362
pii: S0085-2538(21)00921-2
doi: 10.1016/j.kint.2021.08.031
pmc: PMC8608748
mid: NIHMS1748319
pii:
doi:
Substances chimiques
Fatty Acids
0
Klf15 protein, mouse
0
Kruppel-Like Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1250-1267Subventions
Organisme : BLRD VA
ID : I01 BX005300
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112984
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK113223
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007757
Pays : United States
Organisme : BLRD VA
ID : I01 BX003698
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121846
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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